Amino-derivatives of 1,2-benzothiazine dioxides

ABSTRACT

THE COMPOUNDS HEREIN 1,2,3,4-TETRAHYDRO-11:HYDROXYPYRAZINO(1,2-B)-1,2-BENZOTHIAZIN-1(2H)-ONE-6,6 -DIOXIDES, USEFUL FOR THEIR ULTRA-VIOLET ABSORPTION AND PHARMACOLOGICAL PROPERTIES.

United States Patent Ice 313,212:

to'enhance the rate of reaction. The reaction may be 3,787,403 illustrated by the following: AlVlINO-DERIVA'IIVEgygh}; lg-BENZO'IHIAZINE DI E o Chris Royce Rasmussen, Ambler, Pa., assignor to 5 0 McNeil Laboratories, Inc. No Drawing. Filed Oct. 2, 1972, Ser. No. 294,122 N Int. Cl. C07d 93/02 US. Cl. 260-243 R 7 Claims N RH (I) 10 80: ABSTRACT OF THE DISCLOSURE The compounds herein are 1,2,3,4-tetrahydro-11-hy- The compounds of Formula I absorb ultra-violet droxypyrazino[1,2-b]-1,2-benzothiazin-1(2 El)-one 6,6-di- (U.V.) light above 300 nm. and are useful as U.V. screenoxides, useful for their ultra-violet absorption and phar- 5 materials f as for their pharmacological propm l i l properties 15 erties. Table I indicates the UV. absorption of representative compounds embraced within Formula I.

DESCRIPTION OF THE INVENTION TABLE I This invention relates to novel 1,2,3,4-tetrahydro-11- R y ypy fl1,2-b]-1,2-benzothiazin-1(2g)-one 6,6- m 11,200 I 343 dioxides and, more particularly, to those having the following formula OH O N-CHzCHzR N CH; 8,700 343 wherein R is a member selected from the group consist- 12-100 342 ing of 4-loweralkylpiperazinyl, anilino, morpholino, di-

loweralkylamino, and piperidino. As used herein, loweralkyl means a straight or branched chain saturated ali- Because of their general solubility in organic materials,

phatic hydrocarbon containing from 1 to about 5 carthe compounds of Formula I may be used as U.V.- bon atoms such as, for example, methyl, ethyl, propyl, absorbers in plastics and resins such as, for example, polyisopropyl, butyl, and the like. styrene, polyethylene, polypropylene, polyacrylics (e.g.,

The compounds of Formula I are made by reacting methacrylate resins, polyacrylamides, polyacrylonitrile (1,2,3,4-tetrahydro 11 hydroxy-l-oxopyrazino[1,2-b]- fibers, etc.), polyamide (e.g., nylon) fibers, and polyester 1,2-benzothiazin-2-yl)ethyl methane sulfonate 6,6-dioxide fibers. The inclusion of about 0. 01-5.0 percent of the (H) which is disclosed in my copending application Ser. absorber, based on the polymer weight, is usually sufli- No. 294,126 entitled Novel 1,2-benzothiazine dioxides cient to render protection against UV. light, such as in and Precursors Thereof, filed on the same date as the plastic films, filters, etc. The absorber may be incorporated instant application, with a 1-2 molar excess of an approinto the mixture of monomers before polymerization to priate amine, RH, in which R is as previously defined. form the polymer or it may be incorporated into the poly- The reaction is conducted in a suitable organic solvent mer at other stages during its handling, as by milling into such as, for example, an ether, e.g., ethyl ether, dioxane, the polymer together with other compounding ingredients, tetrahydrofuran, and the like; a lower alkanol, e.g., ethor during the spinning of the polymer into fibers, etc.

anol, isopropanol, butanol, and the like; dimethylsulfox- These compounds are also useful for their pharmaide; dimethylformamide; and the like. Elevated tempera- Cological p p For p when R=al1i1iI10 tures may be employed to enhance the rate of reaction. morpholillo, a dose of about 1118/ y Weight The reaction may be illustrated by h following; i.p. produces ataxia in the mouse, which is indicative of central nervous system depressant activity. Furthermore,

V when R=piperidino, an oral dose of about 100 mg./kg. 0H 0 bodyweight is observed to produce 30% inhibition in the conventional kaolin-induced rat paw edema assay, which indicates anti-inflammatory activity.

The following examples are intended to illustrate, but not to limit, the scope of the present invention.

EXAMPLE I 1,2,3,4-tetrahydro-1l-hydroxy-2-[2-(4-methyl 1 piperlthl 'ol,2-b-1,2-b A second method of preparing the compounds of Forfi gg g enzothlazm mula I is by reacting a slight molar excess of an appropriate amine (RH) with 2,3,5,6-tetrahydro-13g-oxazolo To a stirred solution of 10.38 g. (0.132 mole) of N [2',3:3,4]pyrazino[l,2-b]-1,2-benzothiazin l3 (2g)- methylpiperizine in 75 ml. of dimethylformamide is added one 8,8-dioxide (III), also described in my previously -20 g. (0.051 mole) of (l,2,3,4-tetra-hydro-ll-hydroxy-lmentioned copending application Ser. No. 294,126. This oxopyra'zino[1,2-b]-1,2-benzothiazin-2-yl)ethyl methanereaction is conducted in a suitable organic solvent as desulfonate 6,6-dioxide. After the mixture has been heated scribed above and elevated temperatures may be employed on a steam bath for 2 hours, the solvent is removed in vacuo and water is added to the residue. The resulting crude product (M.P. 163-165 C.) is collected and recrystallized from acetone-water yielding the pure product, 1,2,3 ,4-tetrahydro-1 1-hydroxy-2- [2- (4-methy1- lpiperizinyl)ethyl]pyrazino[1,2 b 1,2 benzothiazin- 1(2g)-one 6,6-dioxide, M.P. 165166 C.

Analysis.-Calcd. for C H N O S (percent): C, 55.08; H, 6.16; N, 14.28. Found (percent): C, 55.18; H, 6.04; N, 14.41.

EXAMPLE II 2 (2 anilinoethyl) 1,2,3,4 tetrahydro 11 hydroxypyrazino[1,2 b] 1,2 benzothiazin 1(2 Il) one 6,6-dioxide To a stirred slurry of 7.77'g. (0.02 mole) of (1,2,3,4- tetrahydro 11 hydroxy 1 oxopyrazino[1,2-b]-1,2- benzothiazin-2-yl)ethyl methanesulfonate 6,6-dioxide in 8 ml. of dry dimethylformamide is added 5.58 g. (0.06 mole) of aniline, followed by a rinse of dry dimethylformamide. The reaction mixture is stirred at ambient temperatures for 3 hours and is then heated on a steam bath for about 15 hours. After the heating is finished, the excess dimethylformamide is removed in vacuo, and the brown, oily residue is triturated with water. Crystallization of the product is caused by decanting the Water and adding a slight amount of acetone to the remaining residue. Further crystallization is stimulated by trituration with ethyl other after removal of the initial product, yielding a crude ta-n product, M.P. 140-142 C. Recrystallization from acetone-ethyl ether yields the pure product, 2 (2 anilinoethyl) 1,2,3,4 tetrahydro 11-hydroxypyrazino[1,2 b] 1,2, benzothiazin 1(2g)-one 6,6-dioxide, M.P. l43144 C.

Analysis.-Calcd. for C H N O S (percent): C, 59.21, H, 4.97; N, 10.90. Found (percent): C, 59.37; H, 4.81; N, 10.73.

EXAMPLE III 1,2,3,4 tetrahydro 11 hydroxy 2 (2 morpholinoethyl)pyrazino[1,2 b] 1,2 benzothiazin -1(2- one 6,6-dioxide The procedure of Example I is reepated, except that an equivalent amount of morpholine is substituted for the N- methylpiperizine used therein, yielding the desired product, 1,2,3,4 tetrahydro 11 hydroxy-Z-(Z-morpholinoethyl)pyrazino[1,2 b] 1,2 benzothiazin-1(2g)-one 6,6-dioxide, M.P. 152-153 C.

Analysis.-Calcd. for C H N 'O S (percent): C, 53.81; H, 5.58; N, 11.08. Found (percent): C, 54.14; H, 5.50; N, 10.93.

EXAMPLE IV 2 2 dimethylarninoethyl) 1,2,3,4 tetrahydro 11- hydroxypyrazino[1,2 b] 1,2 benzothiazin 1(2H)-' one 6,6-dioxide To a stirred saturated solution of dimethylamine in 50 ml. of dimethylformamide is added 20.0 g. (0.0515 mole) of (1,2,3,4-tetrahydro-1l-hydroxy-l-oxopyrazino- [1,2 b] 1,2 benzothiazin-2-yl)ethyl methanesulfonate 6,6-dioxide and the solution is again saturated with dimethylamine and is heated on a steam bath for 1 hour. After the solvent and excess dimethylamine are removed in vacuo, the residue is dissolved in 1.3 N hydrochloric acid and is precipitated with sodium hydroxide. Upon dissolving the resulting gummy solid in acetonewater, crystallization occurs, yielding the crude product, M.P. 102105 C. Recrystallization from acetone-water yields the pure product, 2-(Z-dimethylaminoethyl)-1,2,3, 4-tetrahydro 11 hydroxy 2 [(2 dimethylamino) ethyl]pyrazino[1,2 b] 1,2 benzothiazin 1(2 Ig)-one 6,6-dioxide, M.P. 105107 C.

Analysis.Calcd. for C H N O S (percent): C, 53.40; H, 5.68; N, 12.45; S, 9.50. Found (percent): C, 53.47; H, 5.78; N, 12.24; S, 9.68%.

4 EXAMPLE v 1,2,3,4 tetrahydro 11 hydroxy 2 (2 piperidinoethyl)pyrazino[1,2 b] 1,2 benzothiazin 1(2 1 I one 6,6-dioxide A solution of 6 g. (0.0205 mole) of 2,3,5,6-tetrahydro- 13g oxazolo[2',3':3,4]pyrazino[1,2 b] 1,2 benzothiazin-13(2 Il)-one 8,8-dioxide and 2.13 g. (0.025 mole) of piperidine in 40 ml. of dimethylformamide is heated on a steam bath for 1.5 hours, after which time the solvent is removed in vacuo. To the residue is added 25 ml. of 10% sodium carbonate solution, and the resulting solid is filtered olf, yielding crude product. This crude EXAMPLE VI The procedure of Example I is repeated except that an equivalent amount each of diethylamine and dipropylamine is used in place of the N-methylpiperizine used therein to yield as respective products:

2-(diethylaminoethy1)-1,2,3,4-tetrahydro-1l-hydroxypyrazino 1,2-b]-1,2-benzothiazin-1 (211) -one 6,6-dioxide, and

2- (dipropylaminoethyl) -1,2,3,4-tetrahydro-1 l-hydroxypyrazino[ 1,2-b]-1,2-benzothiazin-1 (2 E I -one 6,6-dioxide.

What is claimed is:

1. A 1,2,3,4 tetrahydro-11-hydroxypyrazino[1,2-b]- 1,2-benzothiazin-1(ZIP-one 6,6-dioxide having the formula:

N-CHzC HzR wherein R is a member selected from the group consisting of 4-methylpiperazinyl, anilino, morpholino, diloweralkylamino, and piperidino.

2. 1,2,3,4 tetrahydro 11 hydroxy-2-[2-(4-methyl-1- piperazinyl)ethyl] pyrazino[1,2-b] 1,2 benzothiazin- (2g)-one 6,6-dioxide.

3. 1,2,3,4 tetrahydro 11 hydroxy-2-(2-anilinoethyl) pyrazino[1,2-b]-1,2-benzothiazin 1(2g) one 6,6-dioxide.

4. 1,2,3,4 tetrahydro-11-hydroxy-2-(2-morpholinoethyl)pyrazino[1,2-b] 1,2 benzothiazin-1(2II )-one 6,6- dioxide.

5. 2 (2 diloweralkylaminoethyl) 1,2,3,4 tetrahydro-1l-hydroxypyrazinoELZ-b]-1,2-benzothiazin H211)- one 6,6-dioxide.

1 6. 2 (2 dimethylaminoethyl)-1,2,3,4-tetrahydro-11- hydroxypyrazino[1,2-b] 1,2 benzothiazin-1(2I )-one 6,6-dioxide.

7. 1,2,3,4 tetrahydro-11-hydroxy-2-(2-piperidinoethyl)pyrazino[1,2-b] 1,2 benzothiazin-1(2g)-one 6,6-dioxide.

References Cited UNITED STATES PATENTS 3,408,347 10/1968 Shavel et a1. 260--243 JOHN M. FORD, Primary Examiner US. Cl. xn. 

